U.S. Pat. No. 4,446,113, European Patent Publication No. 95316 and European Patent Publication No. 277,612 disclose benzopyran compounds having antihypertensive actions, smooth muscle-relaxant actions and the like. Moreover, European Patent Publication No. 339,562, discloses that the novel benzopyran compounds bearing a N-acyl-N-oxy-substituted amino group or a hydrazine group at the 4-position, possess hypotensive, coronary blood flow-increasing activities and the like.
Recently, in developing a compound having a chiral carbon atom(s) as drug, the corresponding optical isomer (eutomer) has become important from the view point of enhancement of the pharmacological activity, removal of the side effect, lowering of the toxicity, simplification of absorption, distribution, metabolism or excretion or improvement of the solubility and the like.
The optically active benzopyran compounds which are expected to have such improved characteristics are disclosed in, for example, European Patent Publication No. 120,428 and European Patent Publication No. 314,446.
In the above mentioned patent applications, such optically active benzopyran compounds as an end product compounds by reacting the corresponding racemate with a chiral isocyanate such as (-)-.alpha.-methylbenzylisocyanate, and then resolving the diastereomers thus obtained by chromatography or fractional crystallization. However, such chiral isocyanates are so hardly available that such method is not practical from the industrial point of view.
On the other hand, the method employing an optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compound as a starting compound is disclosed in British Patent Publication No. 2,204,868 and European Patent Publication No. 344,747. In British Patent Publication No. 2,204,868, there is disclosed that optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compounds can be obtained by reacting trans-3-bromo-2,2-dimethyl-4-hydroxy-2H-1-benzopyran-6-carbonitri le with (-)-camphanic acid, subjecting the mixture of the obtained diastereomers to silica gel chromatography and then subjecting each of diastereomers to hydrolysis. However, (-)-camphanic acid itself is very expensive, and further, the resolution operation of diastereomers by chromatography consumes a long period of time, a lot of solvents and carriers. In brief, such operation is expensive and complicate, and is not suitable for resolution on a large scale.
In European Patent Publication No. 344,747, there is disclosed that optically active 3,4-dihydro-3,4-epoxy-2H-1-benzopyran compounds can be obtained by reacting 2,2-dimethyl-2H-1-benzopyran with N-bromosuccinimide and N-benzyloxycarbonyl-L-alanine chloride and then subjecting the obtained (3R,4S)-4-{(2S)-2-benzyloxycarbonylaminopropionyloxy}-3-bromo-3,4 -dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile to cyclization by hydrolysis.
Therefore, the development of a practically useful method for the optical resolution has been desired.